Download Review of Vasodilators in Acute Decompensated Heart Failure

Journal of Cardiac Failure Vol. 19 No. 7 2013
Review Articles
Review of Vasodilators in Acute Decompensated Heart Failure:
The Old and the New
MICHELLE D. CARLSON, MD,1 AND PETER M. ECKMAN, MD2
Minneapolis, Minnesota
ABSTRACT
Despite substantial improvements in treatment for chronic heart failure, morbidity and mortality for acute
decompensated heart failure (ADHF) remain high. Treatment of ADHF is focused on controlling
symptoms rather than improving long-term outcomes. The vasodilators nitroglycerin (NTG) and sodium
nitroprusside (SNP) have been used in ADHF for decades, but, since the development of nesiritide 10
years ago, interest in new vasodilators has grown. Therapies that improve not only hemodynamics and
symptoms but also long-term outcomes are in high demand, and numerous new vasodilatory agents
have been investigated, including various natriuretic peptides, soluble guanylyl cyclase agents, reninangiotensin-aldosterone systememodifying agents, and others. A review of the literature shows that
few of them rise to the challenge set by NTG and SNP. (J Cardiac Fail 2013;19:478e493)
Key Words: Nitroglycerin, sodium nitroprusside, natriuretic peptide.
Almost 1 million patients yearly receive a primary diagnosis of acute decompensated heart failure (ADHF) at hospital discharge in the United States (US),1 with the direct
cost of these hospitalizations reaching $209 billion in
2010.2 In-hospital mortality varies among recent registries
from w3% to 5%,3,4 a decrease from the 8% rate found
in a Medicare beneficiary registry from 1991 to 1994,5
but long-term statistics remain bleak, with rehospitalization
rates of 25%e40% and post-hospitalization mortality rates
of 10%e20% 2e3 months after discharge.3,6,7
ADHF results in poor outcomes for many reasons, including the natural course of the disease and the age and comorbidities of those most affected,1,8 with a paucity of
treatment shown to decrease morbidity and mortality.3
Management of ADHF focuses on improving symptoms
by relieving congestion rather than improving long-term
outcomes, which may be appropriate to a certain extent:
[B]oth patients and physicians desire therapies that improve signs, symptoms, and/or quality of life, assuming
an acceptable safety profile. Expecting therapies used
for 48 hours to improve outcomes at 2 to 6 months in
a complex, heterogeneous substrate [.] may set the
bar too high.9
ADHF is a complex syndrome rather than a single pathologic entity, aising from a variety of etiologies manifesting
as diverse clinical presentations in patients with systolic
dysfunction as well as in those with preserved ejection
fraction (EF).8,10,11 Various forces are involved in the
pathophysiology of ADHF, ranging from molecular and
immunologic disturbances to ischemic and mechanical
dysfunction.12 Many of these derangements are driven
by neurohormones, including the renin-angiotensinaldosterone system (RAAS), the sympathetic nervous
system, antidiuretic hormone (ADH), natriuretic peptides
(NPs), and endothelins.12,13 As shown in Figure 1, neurohormones can affect cardiac function either directly or by
modulating preload, afterload, natriuresis, and diuresis. In
ADHF, many neurohormones are elevated, resulting in
increased afterload and preload, decreased natriuresis and
diuresis, and decreased ventricular contractility.12e14
First-line management for ADHF consists of intravenous
diuretic therapy, which improves ventricular contraction
and decreases heart failure (HF) symptoms via natriuresis
and diuresis. Heart Failure Society of America (HFSA)
From the 1Department of Medicine, University of Minnesota Medical
School, Minneapolis, Minnesota and 2Division of Cardiology, University
of Minnesota Medical School, Minneapolis, Minnesota.
Manuscript received August 16, 2012; revised manuscript received May
14, 2013; revised manuscript accepted May 16, 2013.
Reprint requests: Michelle D. Carlson, MD, Department of Medicine,
University of Minnesota Medical School, 420 Delaware St SE, Mayo
MMC 284, Minneapolis, MN 55455. Tel: þ1 952 210 3997; Fax: þ1
612 625 3238. E-mail: [email protected]
See page 490 for disclosure information.
1071-9164/$ - see front matter
Ó 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cardfail.2013.05.007
478
Vasodilators in ADHF
Fig. 1. Neurohormonal effects on cardiac function.12e14,16 In
acute decompensated heart failure, the RAAS, the SNS, ADH,
and ET1 act to increase preload and afterload and decrease natriuresis and diuresis, thereby decreasing ventricular contraction.
NPs counteract these effects, improving ventricular contractions
via vasodilatation. ADH, antidiuretic hormone; ET1, endothelin1; NPs, natriuretic peptides; RAAS, renin-angiotensinaldosterone system; SNS, sympathetic nervous system.
guidelines suggest considering a vasodilator for symptoms
of congestion, particularly in the setting of acute pulmonary
edema or severe hypertension.15 As illustrated in Figure 2,
most vasodilators act via cyclic guanosine monophosphate
(cGMP) to increase intracellular calcium, thereby causing
smooth muscle relaxation and vasodilation.16 This results
in decreased preload and afterload, thereby causing improved contractility.12 A combination of diuretic and vasodilator therapy has also been shown to rapidly decrease
neurohormonal activation, including NPs, endothelin, and
norepinephrine.14
Clinical society practice guidelines specifically mention
the vasodilators nitroglycerin (NTG) and sodium nitroprusside (SNP), which have been used in ADHF for 30 years,
and nesiritide, which has been in use for a decade.10,15 Numerous new vasodilatory agents have been developed and
Carlson and Eckman
479
investigated in the past 10 years in the search for therapies
that might improve not only hemodynamics and symptoms
but long-term outcomes as well. We reviewed published
randomized controlled trials (RCTs) and selected observational trials of vasodilators used in the management of
ADHF, including nitric oxide (NO) donators, NPs, soluble
guanylyl cyclase (sGC) agents, RAAS-modifying agents,
endothelin antagonists, relaxin, and hydralazine. Appraisal
of the literature shows that few agents rise to the challenge
set by NTG and SNP.
Methods
Pubmed was searched from 1982 to the present for experimental clinical trials in humans with ADHF reporting relevant clinical
outcomes with the use of the phrase (‘‘heart failure’’ NOT
chronic) AND ‘‘drug name.’’ The following drug names were
used: ‘‘aliskiren,’’ ‘‘BAY 58-2667,’’ ‘‘carperitide,’’ ‘‘CD-NP,’’
‘‘cinaciguat,’’ ‘‘enalapril,’’ ‘‘hydralazine,’’ ‘‘nesiritide,’’ ‘‘nitroglycerin,’’ ‘‘nitroprusside,’’ ‘‘tezosentan,’’ ‘‘relaxin,’’ ‘‘ularitide,’’
and ‘‘urodilatin.’’ The search was limited to articles in the English
language. References from potentially relevant articles and from
review articles were searched to identify additional studies. Clinicaltrials.gov was searched for ongoing trials, and manufacturers
of the various drugs were contacted directly to request information
regarding current and ongoing trials. ADHF was defined as worsening of HF signs or symptoms requiring hospitalization and intravenous therapy (the signs and symptoms reported varied among
trials). Relevant clinical outcomes included hemodynamic effects,
change in dyspnea or clinical status, change in creatinine (Cr),
worsening HF, total or cardiovascular (CV) mortality, and readmission. Trials that focused solely on pharmacodynamics, pharmacokinetics, and safety were excluded. The quality of each
trial was assessed based on randomization, blinding, and handling
of patient attrition in analysis with the use of the Jadad scale.17 A
trial with a Jadad score of $3 was considered to be of reasonable
Fig. 2. Mechanisms of action of selected vasodilators.13,16,20,21,29,56,78 NO and nitrates diffuse across the cell membrane and convert GTP to
cGMP via sGC bound to a reduced heme moiety. cGMP increases intracellular calcium, thereby resulting in smooth muscle relaxation and
vasodilatation. Cinaciguat acts via sGC bound to an oxidized heme moiety or with no heme moiety, while NPs act via membrane-bound
pGC. Relaxin binds RXFP1, a G-coupled protein receptor, to activate NOS3 and increase intracellular NO. cGMP, cyclic guanosine monophosphate; Ga, guanine nucleotide-binding protein; GTP, guanosine triphosphate; NPs, natriuretic peptides; NO, nitric oxide; NOS3, endothelial nitric oxide synthase; PDE, phosphodiesterase; pGC, particular guanylyl cyclase; RXFP1, relaxin/insulin-like family pepide
receptor 1; sGC, soluble guanylyl cyclase.
480 Journal of Cardiac Failure Vol. 19 No. 7 July 2013
quality. Table 1 provides a summary of pertinent clinical trials,
and Table 2 presents drug dosing. Forest plots were constructed
for the relative risks of selected clinical outcomes, including
improvement in dyspnea in Figure 3 and mortality, readmission,
intubation, and/or myocardial infarction (MI) in Figure 4.18
Results
Description of Studies
Twenty-three completed RCTs and 5 RCTs in process
met the inclusion criteria. Three observational trials of interest were also selected. See Table 1 for characteristics
of the included studies.
Nitric Oxide Donators
Intravenous Nitroglycerin. Originally used for the
treatment of angina and acute coronary syndrome (ACS),
NTG was first investigated in ADHF in the early 1980s.19
It is an NO prodrug that activates sGC when it is bound
to a reduced heme moiety.20 The hemodynamic effects of
NTG have been well characterized, including decreased
preload at any dose, decreased afterload at high doses, decreased myocardial oxygen consumption, and improved
coronary blood flow, making it particularly appealing in
ACS.20,21 Adverse effects include neurohormonal activation, headache, and hypotension, and the duration of
infusion is limited by tachyphylaxis. The American College of Cardiology (ACC), American Heart Association
(AHA), HFSA, and European Society of Cardiology
(ESC) all recommend NTG for patients with symptomatic
fluid overload without hypotension or for normotensive patients not responding appropriately to intravenous diuretics
and standard oral therapies.10,15,22 It may be optimal for use
in patients with hypertension, ischemia, or significant
mitral regurgitation.10 Despite longstanding and widespread use in ADHF, a search of the literature revealed
only 1 RCT.23
An open-label RCT in patients with ADHF presenting to
the emergency department (ED) randomized participants to
high-dose isosorbide dinitrate (ISDN) plus low-dose furosemide or to high-dose furosemide plus low-dose ISDN until
oxygen saturation (SpO2) increased to 86% or mean arterial
pressure (MAP) decreased by 30% or to !90 mm Hg.23
The high-dose ISDN group received doses that were presumed to be large enough to decrease preload and afterload,
whereas the high-dose furosemide group received ISDN
doses that were intended to be sufficient to decrease preload
alone.24 In general, participants were quite hypoxic and
hypertensive at presentation (mean SpO2 79%, mean
MAP 128 mm Hg). The primary outcome, a composite
of in-hospital all-cause mortality, intubation within 12
hours, or MI within 24 hours, occurred in 25% of the
high-dose ISDN and 46% of the high-dose furosemide
group (P 5 .041).
An observational trial of early ED-initiated NTG therapy
observed a 14% rate of intubation within 6 hours in the
intervention group compared with 27% in the control
group receiving standard therapy for ADHF (no P value
reported).25 In secondary outcomes, only 38% of NTGtreated patients required intensive care unit (ICU) admission compared with 80% of control patients. Although
patients were quite hypertensive at presentation (mean
MAP 154 mm Hg), the rate of baseline hypoxia was lower
than in the Cotter study (mean SpO2 94%).
Aziz et al retrospectively reviewed patients with chronic
kidney disease admitted with ADHF and divided them into
those treated with NTG and diuretics, those treated with diuretics alone, and those who received neither therapy in the
ED.26 There was no significant difference among the groups
for the primary composite end point (combined 30-day
readmission and 24-month all-cause mortality) or for the
secondary end point of 30-day readmission. In safety end
points, 24-month survival was significantly greater in the
NTG group (87% vs 82% in the diuretic group and 79%
in the group receiving no therapy; P 5 .0001). These
data are clouded by the significantly higher blood pressure
(BP) in the NTG group, because lower BP on presentation
is a well known marker for poor outcomes in ADHF27
(mean 6SD systolic blood pressure [SBP] 150 6 21 mm
Hg in the NTG group, 125 6 19 mm Hg in the group receiving only diuretics, and 125 6 18 mm Hg in the group
receiving no diuretics; P 5 .001).
Despite evidence of improved clinical outcomes with
NTG therapy in hypertensive patients with ADHF, no large
randomized double-blinded placebo-controlled trial has
been performed. Because NTG has become accepted as
a standard of care, sufficient equipoise may not exist for
a placebo-controlled trial, and absence of patent protection
and low cost are likely to ensure that other targets will receive higher priority for funding. On the other hand, recent
attention to comparative effectiveness research and interest
in cost containment for HF treatment at a federal level may
provide options for support of such a trial. No current studies of intravenous NTG in ADHF are listed at Clinicaltrials.gov (accessed February 19, 2013).
Sodium Nitroprusside. SNP was originally used for
post-MI left ventricular (LV) failure in the mid-1970s.28
It has the same mechanism of action as NTG, but hemodynamically it produces an equivalent decrease in preload and
afterload, decreases myocardial oxygen demand, and increases stroke volume and cardiac output (CO).28e30 Adverse effects include hypotension, possible coronary steal,
and ventilation-perfusion mismatching, likely due to pulmonary arteriolar dilatation in nonventilated areas.21 SNP
is light sensitive and should be hung in a protective cover.
Low infusion rates can actually result in inactivation within
intravenous tubing. Tachyphylaxis is not a consideration,
but cyanide toxicity can occur with prolonged infusions
(usually O72 hours) or in the presence of renal dysfunction. This can be avoided with concomitant sodium thiosulfate infusion, of which there is unfortunately a national
shortage.31 According to clinical guidelines, SNP can
be used in situations similar to NTG, and ACC/AHA
guidelines specifically suggest its use in patients with
Table 1. Characteristics and Limitations of Selected Trials of Vasodilator Therapy in Acute Decompensated Heart Failure
Intervention (n)
Trial
Nitroglycerin
Cotter23
Levy25
Aziz26
Sodium nitroprusside
Hockings32
33
Cohn
Mullens34
Nesiritide
NSG efficacy trial37
NSG comparative trial37
VMAC44
ROSE-HF54
Carperitide
Kitashiro61
PROTECT63
Urodilatin
SIRIUS II68
Composite of mechanical ventilation at 12 h,
MI at 24 h, and death in hospital
Y with HD ISDN
HD NTG (29);
Standard therapy (45)
NTG/diuretics (46);
Diuretics (127);
Neither therapy (257)
Intubation at 6 h
Y with HD HTN
Composite of readmission at 30 d and
all-cause mortality at 24 mo
NS
SNP (25);
Furosemide (25)
SNP (407);
Placebo (405)
SNP (78);
No SNP (97)
D in hemodynamics at 1 h*
Y PCWP, Y SVR, [ CI with SNP
All-cause mortality at 48 h, 21 d, and 13 wk*
NS for any time point
All-cause mortality;
cardiac transplant;
all-cause mortality/cardiac transplant;
readmission for HF
Y with SNP, NS;
Y with SNP, NS
LD nesiritide (43);
HD nesiritide (42);
Placebo (42)
LD nesiritide (103);
HD nesiritide (100);
Standard therapy (102)
Nesiritide (204);
NTG (143);
Placebo (142)
Nesiritide (3,496);
Placebo (3,511)
D in PCWP at 6 h
Dose-dependent Y with nesiritide
Global clinical status, dyspnea, and fatigue
evaluated at 6 h, 24 h, and the
end of therapy*
Coprimary end points:
D in PCWP at 3 h (patients with PAC);
D in dyspnea at 3 h (all patients)
Coprimary end points:
D in dyspnea at 6 h;
D in dyspnea at 24 h;
all-cause mortality/HF readmission at 30 d
Efficacy: cumulative urine volume at 72 h;
Safety: D in cystatin C at 72 h
NS for any outcome
Carperitide (18);
Placebo (18)
Carperitide (29);
Standard therapy (29)
Carperitide (26);
Standard therapy (23)
D in hemodynamics at 48 h;
NYHA functional class and echo
parameters at 4 wk*
CV death or readmission*
Coprimary end points:
D in PCWP at 6 h;
D in dyspnea at 6 h
NS;
NS;
NS
Small size, open-label, HD ISDN group
received higher doses of furosemide than
specified (3)
Small size, observational, designed as feasibility
study with no subsequent RCT (NA)
Observational, patients in the NTG group were
more likely to have a history of HF and to be
hypertensive at presentation (NA)
Small size, open-label, limited to patients
with MI (2)
Slightly underpowered to detect a mortality
difference, limited to patients with MI (5)
Observational, hemodynamics significantly
different at baseline, both groups received
various inotropes, medication doses not
reported (NA)
Patients and clinicians scoring symptoms and
global clinical status may have been aware of
hemodynamic effects (5)
Open-label (3)
Nesiritide group more likely to receive
concomitant inotrope therapy, NTG dose
was lower than that indicated for ADHF (5)
Statistical analysis by European group found
a significant difference in dyspnea (5)
d
Recruiting participants, goal 360
Y PCWP, [ CI, [ urine volume with
carperitide
Y PCWP with carperitide;
Y NHYA functional class with carperitide
Small, unclear blinding (2)
Y with carperitide
Small, open-label, control group more likely
to have NYHA functional class IV at
baseline, not powered to detect a mortality
difference (2)
Y with MD and HD ularitide;
Y with all ularitide doses
No follow-up of adverse events after
hospitalization in this safety trial (5)
Small, open-label, excluded patients with
a history of CAD (2)
(continued on next page)
481
LD ularitide (60);
MD ularitide (53);
HD ularitide (55);
Placebo (53)
D in hemodynamics at 48 h*
Y with nesiritide;
Y with nesiritide and NTG
Comments (Jadad Score)
Carlson and Eckman
Kasama
HD ISDN/LD furosemide (52);
LD ISDN/HD furosemide (52)
LD nesiritide;
LD dopamine;
Placebo
Results
62
Primary End Point
Vasodilators in ADHF
ASCEND-HF53
Control (n)
Trial
Control (n)
69
TRUE-AHF
Cinaciguat
Erdmann81
COMPOSE-1
82
COMPOSE-282
COMPOSE-EARLY
82
Enalaprilat
Annane88
Podbregar89
Aliskiren
ASTRONAUT93
Tezosentan
RITZ-1100
RITZ-299
101
RITZ-4
RITZ-5102
103
VERITAS-1,2
Relaxin
Pre-RELAX-AHF107
RELAX-AHF-1108
Hydralazine
GALACTIC112
Primary End Point
Results
Comments (Jadad Score)
Ularitide;
Placebo
Moderate or marked improvement in global
assessment at 6, 24, and 48 h
d
Recruiting participants, goal 2,116
Cinaciguat (97);
Placebo (51)
MD cinaciguat (9);
Placebo (3)
LD cinaciguat (3);
Placebo (1)
MD cinaciguat (9);
Placebo (3)
D in PCWP at 8 h
Y with cinaciguat
D in PCWP at 8 h
Descriptive Y PCWP with cinaciguat
D in PCWP at 8 h
No statistical analysis performed
D in dyspnea at 8 h
Descriptive analysis showed NS
Terminated early owing to high incidence of
hypotension in the cinaciguat group (3)
Terminated early owing to high incidence of
hypotension in the cinaciguat group (3)
Terminated early owing to difficulty with
recruitment, concern for timely completion (3)
Terminated early owing to high incidence of
hypotension in the cinaciguat group (3)
Enaprilat (11);
Placebo (9)
Enalaprilat bolus (10);
Enalaprilat infusion (10)
Hemodynamic changes at various
time points*
Decrease in PCWP by 20% at 30 min
Y PCWP, Y MAP, Y MPAP, [ RBF
with enalaprilat
NS
Aliskiren (808);
Placebo (807)
CV mortality or HF readmission at 6 mo
NS
Recruitment stopped early owing to results of
ALTITUDE, required power was calculated
to have been reached (3)
Tezosentan (331);
Placebo (338)
Tezosentan (191);
Placebo (94)
Tezosentan (97);
Placebo (95)
D in dyspnea at 24 h
NS
(insufficient data to calculate Jadad score)
D in CI at 6 h
Y CI with tezosentan
(5)
Composite of all-cause mortality, worsening
HF, recurrent ischemia, and recurrent
MI at 72 h
D in SpO2 at 1 h
NS
All patients had ACS at presentation in addition
to ADHF (3)
NS
(2)
Coprimary end points:
D in dyspnea over 24 h;
all-cause mortality or worsening HF at 7 d
NS;
NS
Terminated early owing to lack of efficacy (4)
Relaxin, various doses (173);
Placebo (61)
Relaxin;
Placebo
D in dyspnea at 6, 12, and 24 h*
Y with 30 mg kg1 d1 relaxin
Exploratory dose-finding study (5)
Coprimary end points:
D in dyspnea at 6, 12, and 24 h;
D in dyspnea over 5 d
d
Completed, results not published, goal 1,160
NTG, hydralazine, ACE-I/ARB;
Standard therapy
HF death and readmission
d
Recruiting, goal 700
Tezosentan (97);
Placebo (95)
LD tezosentan (730);
Placebo (718)
Small, no safety end points reported (3)
Small, open-label, no placebo, no safety end
points reported (1)
ACE-I, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; ADHF, acute decompensated heart failure; ARB, angiotensin-receptor blocker; CAD, coronary artery disease; CI, cardiac
index; CV, cardiovascular; HD, high-dose; HF, heart failure; ISDN, isosorbide dinitrate; LD, low-dose; MD, moderate-dose; MI, myocardial infarction; NA, not applicable; NS, no significant difference;
NSG, nesiritide study group; NTG, nitroglycerin; NYHA, New York Heart Association; PAC, pulmonary artery catheter; PCWP, pulmonary capillary wedge pressure; RCT, randomized controlled trial; SNP,
sodium nitroprusside.
*Primary end point not specified.
482 Journal of Cardiac Failure Vol. 19 No. 7 July 2013
Table 1. (Continued )
Intervention (n)
Table 2. Dosing Regimens in Selected Trials of Vasodilator Therapy in Acute Decompensated Heart Failure
Study
Intervention
Nitroglycerin
Cotter23
Levy25
Aziz26
Sodium nitroprusside
Hockings32
Cohn33
Mullens34
Nesiritide
NSG efficacy trial37
37
NSG comparative trial
COMPOSE-1
COMPOSE-282
COMPOSE-EARLY82
Enalaprilat
Annane88
Podbregar89
Aliskiren
ASTRONAUT93
Tezosentan
RITZ-1100
RITZ-299
RITZ-4101
RITZ-5102
VERITAS-1,2103
Relaxin
Pre-RELAX-AHF107
RELAX-AHF-1108
Hydralazine
GALACTIC112
Peak SNP 235 mg/min IV infusion
Mean SNP 92.3 mg/min IV infusion at 24 h, 94.4 mg/min IV infusion at 48 h
SNP 10e400 mg/min IV infusion; mean dose not reported
Mean furosemide 440 mg IV bolus
Placebo
Standard therapy without SNP
Nesiritide 0.3 mg IV bolus, then 0.015 mg kg1 min1 IV infusion or 0.6 mg IV bolus,
then 0.03 mg kg1 min1 IV infusion
Nesiritide 0.3 mg/kg IV bolus, then 0.015 mg kg1 min1
IV infusion or 0.6 mg IV bolus, then 0.03 mg kg1 min1 IV infusion
Nesiritide 2 mg/kg IV bolus, then 0.01 mg kg1 min1 IV infusion; after 3 h, 23 patients with
PAC had dose titrated to 0.03 mg kg1 min1
Placebo
Standard therapy
Nesiritide 2 mg/kg IV optional bolus then 0.01 mg kg1 min1 IV infusion
Low-dose nesiritide IV infusion
Low-dose dopamine IV infusion
Mean NTG 39 mg/min IV infusion at
3 h without PAC; 42 mg/min IV
infusion at 3 h with PAC
Placebo
Placebo
Carperitide 0.05e0.2 mg kg1 min1 IV infusion; mean dose not reported
Carperitide 25 ng kg1 min1 IV infusion
Carperitide 0.01e0.05 mg kg1 min1 IV infusion; mean 0.024 mg kg1 min1
Placebo
Standard therapy
Standard therapy
Ularitide 7.5, 15, or 30 ng kg1 min1 IV infusion
Ularitide 15 ng kg1 min1 IV infusion
Placebo
Placebo
Cinaciguat 100 mg/h IV infusion initially, titrated from 50 to 600 mg/h; mean dose
not reported
Cinaciguat 50, 100, or 150 mg/h IV infusion
Cinaciguat 10 or 25 mg/h IV infusion
Cinaciguat 50, 100, or 150 mg/h IV infusion
Placebo
Placebo
Placebo
Placebo
Enalaprilat 1 mg IV infusion over 2 h
Enalaprilat 0.004 mg IV bolus or infusion over 1 h
Placebo
NA
Aliskiren 150 mg PO daily, could be increased to 300 mg daily after 2 wk
Placebo
Tezosentan
Tezosentan
Tezosentan
Tezosentan
Tezosentan
Placebo
Placebo
Placebo
Placebo
Placebo
Carlson and Eckman
82
Mean ISDN 1.4 mg IV bolus;
Mean furosemide 200 mg IV bolus
Mean initial NTG 31.7 mg/min to unknown max IV infusion;
Mean furosemide 82.1 mg IV bolus
Mean furosemide 59 mg IV bolus in Mean furosemide dose 52 mg IV
ED, 53 mg IV bolus in hospital
bolus in hospital
ASCEND-HF53
ROSE-HF54
Carperitide
Kitashiro61
Kasama62
PROTECT63
Ularitide
SIRIUS II68
TRUE-AHF69
Cinaciguat
Erdmann81
Mean ISDN 11.4 mg IV bolus;
Mean furosemide 56 mg IV bolus
Mean NTG 6.5 mg IV bolus, then 23.6e50.2 mg/min IV infusion;
Mean furosemide 85.5 mg IV bolus
NTG 5e15 mg/min IV infusion;
Mean furosemide 75 mg IV bolus in ED, 50 mg IV bolus in hospital
Vasodilators in ADHF
VMAC44
Control
50 mg/h IV infusion
50 or 100 mg/h IV infusion
50 mg/h IV infusion
50 or 100 mg/h IV infusion
5 mg/h IV loading dose over 1 h, then 1 mg/h IV infusion
Placebo
Placebo
Sublingual and transdermal nitrates and oral hydralazine
followed by rapid up-titration of ACE-I or ARB
Standard therapy
ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; ED, emergency department; ISDN, isosorbide dinitrate; NA, not applicable; NTG, nitroglycerin; PAC, pulmonary artery
catheter; SNP, sodium nitroprusside.
483
Relaxin 10, 30, 100, or 200 mg/kg/d IV infusion
Relaxin 30 mg/kg/d IV infusion
Placebo; at 3 h patients crossed over
to nesiritide or NTG
484 Journal of Cardiac Failure Vol. 19 No. 7 July 2013
Fig. 3. Relative risk of improvement in dyspnea in selected trials of vasodilator therapy in acute decompensated heart failure. NES, nesiritide; NTG, nitroglycerin; RLX, relaxin; SNP, sodium nitroprusside; URO, urodilatin. References: ASCEND-HF,53 NSG efficacy trial and
comparative trial,37 Pre-RELAX-AHF,107 SIRIUS II,68 VMAC.44
severe volume overload and hypertension or mitral
regurgitation.10,15,22
In an open-label RCT evaluating hemodynamic effects in
patients with LV failure after MI, SNP was associated with
a greater decrease in pulmonary capillary wedge pressure
(PCWP), systemic vascular resistance (SVR), and increase
in cardiac index (CI) at 1 hour compared with furosemide
(9 vs 4 mm Hg, 21% vs þ10%, and þ16% vs
7%, respectively; P ! .001 for all).32 Hemodynamic
differences, except for PCWP, were maintained at 48 hours.
No significant difference in the safety end point of all-cause
mortality at 48 hours or 12 months was noted.
A large multicenter double-blinded randomized trial by
Cohn et al evaluated all-cause mortality for SNP compared
with placebo in patients with LV failure after MI.33 There
was no significant difference in all-cause mortality at
48 hours, 21 days, or 13 weeks, either between treatment
groups or by prespecified subgroups (including age, SBP,
Fig. 4. Relative risk of mortality, readmission, intubation, or MI in selected trials of vasodilator therapy in acute decompensated heart failure. ASK, aliskiren; CAR, carperitide; HF, heart failure; ISDN, isosorbide dinitrate; MI, myocardial infarction; NES, nesiritide; NTG, nitroglycerin; RLX, relaxin; SNP, sodium nitroprusside; URO, urodilatin. References: ASCEND-HF,53 ASTRONAUT,93 Aziz,26 Cohn,33
Cotter,23 Hockings,32 Levy,25 Mullens,34 Pre-RELAX-AHF,107 PROTECT,63 SIRIUS II.68
Vasodilators in ADHF
Carlson and Eckman
485
Fig. 5. Algorithm for management of acute decompensated heart failure.10,11,15,34,112 CXR, chest X-ray; DA, dopamine; DBA, dobutamine;
IV, intravenous; JVD, jugular venous distention; MAP, mean arterial pressure; NT-proBNP, N-terminal prohormone of B-type natriuretic
peptide; NTG, nitroglycerin; PND, paroxysmal nocturnal dyspnea; SpO2, oxygen saturation; SNP, sodium nitroprusside.
and LV filling pressure). The use of diuretics was 45% in
the placebo group versus 11% in the SNP group (P !
.001). As in the study by Hocking et al,32 it is unclear if results in patients with LV failure after MI would generalize
to all patients with acute HF.
An observational study by Mullens et al reviewed patients with ADHF admitted to a specialized HF ICU and
compared those treated with SNP to an MAP goal of
65e70 mm Hg with those who did not receive SNP.34 At
baseline, those who received SNP had significantly higher
central venous pressure (CVP), PCWP, and MAP, and significantly lower CI (P ! .05 for all). Primary end points included all-cause mortality, heart transplant, a combination
of the two, and readmission for HF. There were no significant differences between the 2 groups for heart transplant or
readmission, but those treated with SNP had a lower allcause mortality of 29% compared with 44% in those who
did not receive SNP (P 5 .005), with an early and persistent
separation of survival curves. SNP remained an independent predictor of survival on multivariate analysis. Of
note, in subgroup analysis of those patients with MAP
#85 mm Hg, SNP was still associated with lower allcause mortality (P 5 .0001). There was a nonsignificant
trend toward less inotrope use in the SNP group, raising
the possibility that patients who did not receive SNP were
‘‘sicker.’’ However, this is not supported by the baseline
characteristics, which showed no significant difference between the 2 groups in serum sodium, renal function, or hemoglobin, all markers of HF severity.35 Alternatively,
treatment with SNP may have resulted in clinical improvement and decreased the need for inotropes.
Given this mixed data, a large randomized doubleblinded placebo-controlled trial of SNP for the treatment
of ADHF not due to MI would be of interest. However,
as with NTG, SNP has become a standard of care and is
off patent, making such a trial unlikely. No current studies
of intravenous SNP in ADHF are listed at Clinicaltrials.gov
(accessed February 20, 2013), and the manufacturer of SNP
(Nitropress; Hospira) was not aware of any current or upcoming clinical trials (personal communication, February
25, 2013).
Natriuretic Peptides
Nesiritide. Nesiritide, recombinant human B-type natriuretic peptide (BNP), acts at the natriuretic peptide A receptor (NPR-A) to decrease preload, afterload, and PCWP,
increase CO,21,36e38 increase urine output,37 and improve
diastolic function.39 Adverse effects include headache and
hypotension.37,39 ACC/AHA and HFSA guidelines recommend nesiritide as an alternative therapy to NTG and
SNP that decreases LV filling pressure and improves dyspnea more rapidly than diuretic therapy alone.10,15
The Nesiritide Study Group performed 2 RCTs examining the use of nesiritide in patients with ADHF admitted
for vasoactive therapy.37 The double-blinded placebocontrolledefficacy trial showed a significant, dosedependent decrease in PCWP with nesiritide therapy
(þ2.0 mm Hg with placebo, 6.0 mm Hg with low-dose
nesiritide, and 0.6 mm Hg with high-dose nesiritide;
P ! .001), and secondary outcomes of hemodynamics,
symptoms, and global clinical status were significantly
486 Journal of Cardiac Failure Vol. 19 No. 7 July 2013
improved in a higher percentage of patients in the nesiritide
groups. The open-label comparative RCT demonstrated no
significant difference in global clinical status, dyspnea, and
fatigue at 6 hours, 24 hours, or the end of treatment
for low-dose and high-dose nesiritide infusions versus standard therapy.
The Vasodilatation in the Management of Acute CHF
(VMAC) study, a large double-blinded RCT, compared
the change in PCWP and subjective evaluation of dyspnea
at 3 hours in patients treated with nesiritide, NTG, or
placebo.39 PWCP at 3 hours was significantly decreased
with nesiritide versus NTG and placebo (5.8 mm Hg,
3.8 mm Hg, and 2 mm Hg, respectively; P ! .05),
but by 24 hours there was no difference in PCWP between
the nesiritide and NTG groups. Although dyspnea at 3 hours
was significantly decreased in the nesiritide group versus
placebo (P 5 .03), there was no significant difference between nesiritide and NTG-treated participants. At 3 hours,
placebo patients crossed over to nesiritide or NTG, and
clinical end points were evaluated over the next 6 months.
Although the trial was not powered to detect a reduction in
mortality, there was no significant difference between
groups in MI at 30 days, readmission at 30 days, or mortality at 7 days or 6 months. The study was limited by the fact
that the mean dose of NTG used (39e42 mg/min intravenously [IV]) was far below the optimal NTG dose in the
treatment of ADHF, which is in the range of 120e200
mg/min IV.40 When patients did receive adequate doses of
NTG, as in the subgroup analysis reported by Elkayam
et al (where those treated with NTG received an average
dose of 160 mg/min IV), nesiritide resulted in only a transient significant decrease in PCWP compared with NTG
that disappeared by 30 minutes.41
Approved and widely used on the basis of symptomatic
improvement in the VMAC study, nesiritide appeared to be
safe and effective for use in patients with coronary artery disease,42 those on b-blockers,43 and those with chronic kidney
disease.44,45 The Prospective Randomized Evaluation of Cardiac Ectopy with Dobutamine or Natrecor Therapy (PRECEDENT) trial showed that nesiritide did not carry the
proarrhythmic risks of dobutamine,46 and a subgroup analysis of the Nesiritide Study Group comparative trial found that
it resulted in significantly fewer HF readmissions and lower
6-month all-cause mortality than dobutamine.47 In 2005,
however, 2 meta-analyses by Sackner-Bernstein et al called
into question its safety, showing that nesiritide significantly
increased the risk of worsening renal function compared
with other therapies for ADHF (21% vs 15%; P 5 .001)48
and tended to increase 30-day all-cause mortality (7.2% vs
4.0%; P 5 .059).49 Two subsequent meta-analyses of
RCTs did not show an increase in 30-day or 180-day allcause mortality with nesiritide,50,51 but doubts regarding its
safety remained.
To respond to these concerns, an independent panel was
convened and recommended a large clinical trial to evaluate
the safety and efficacy of nesiritide.52 Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart
Failure (ASCEND-HF), a multicenter randomized doubleblinded placebo-controlled trial, was designed to compare
nesiritide with placebo in patients admitted with ADHF.53
Coprimary outcomes were change in dyspnea at 6 hours
and 24 hours and a composite of 30-day HF rehospitalization and all-cause mortality. Although more nesiritide patients experienced a decrease in dyspnea, the difference
did not reach statistical significance, nor was there a significant difference between the groups in the combined end
point of rehospitalization for HF and 30-day all-cause mortality or in the safety end point of renal dysfunction. These
results were consistent across prespecified subgroups.
Renal Optimization Strategies Evaluation in Acute Heart
Failure (ROSE-AHF), sponsored by the National Heart,
Lung, and Blood Institute, is the only active clinical trial
of nesiritide registered at Clinicaltrials.gov (accessed February 21, 2013). The study is recruiting patients with
ADHF and renal dysfunction and randomizing them to
low-dose dopamine, low-dose nesiritide, or placebo in addition to optimal diuretic dosing as a renal-protective therapy.54 The manufacturer of nesiritide (Natrecor; Scios,
a subsidiary of Johnson & Johnson) did not communicate
regarding any additional current or upcoming clinical trials.
Finally, despite its lack of efficacy in other situations, nesiritide benefits patients with profound renal failure and diuretic resistance following ventriculectomy and placement
of a total artificial heart, because these patients no longer
produce endogenous BNP.55
Carperitide. Carperitide, or A-type natriuretic peptide
(ANP), acts as a stronger agonist than BNP at NPR-A.56 Its
hemodynamic effects are similar to those of nesiritide, although it has more robust natriuretic and diuretic effects
that are more pronounced in healthy subjects than in patients with HF.57,58 It increases and decreases MAP and
PCWP,57,58 and its most common adverse effect is hypotension.59,60 It has been investigated and used extensively in
Japan, where it was approved in 1995,59 whereas American
and European societal clinical guidelines do not address its
use.10,15,22
A small RCT in patients with ADHF resistant to other
therapies showed a decrease in PCWP, an increase in CI,
and an increase in urine volume at 48 hours with carperitide
compared with placebo (10 vs 0 mm Hg, þ0.77 vs þ0.01
L min1 m2, and þ868 vs 63 mL/d, respectively; P !
.005 for all).61 These effects persisted without evidence
of tachyphylaxis after 7 days of infusion.
Kasama et al evaluated patients with new-onset acute
HF who were treated with dopamine and furosemide, and
then randomized to ANP or placebo.62 At 48 hours, CVP
and PCWP decreased and CI increased significantly from
baseline in the carperitide group (3.5 mm Hg, 6.9 mm
Hg, and þ0.5 L min1 m2, respectively; P ! .05 for
all), but only PCWP was significantly lower than in the
placebo group (15 vs 19 mm Hg; P ! .05). Small statistically significant decreases in LV end-diastolic volume, LV
end-systolic volume, EF, and New York Heart Association
(NYHA) functional class in the ANP group were noted at
Vasodilators in ADHF
4 weeks, but only NHYA functional class was significantly
lower than in the placebo group (P ! .05).
Prospective Trial of Cardioprotective Effect of Carperitide Treatment (PROTECT), a multicenter open-label
RCT, evaluated patients with ADHF treated with standard
therapy with or without carperitide.63 The combined end
point of CV mortality and rehospitalization occurred in
12% of the carperitide group vs 35% of the standard therapy group (P 5 .036), but the study was underpowered to
detect a difference in mortality.
Two large cohort studies examined the safety and
efficacy of carperitide and found that it improved subjective
symptoms and hemodynamics in just over 80% of patients.59,60 It was less likely to be effective in patients
with MI, more severe HF, or renal dysfunction. The randomized trials accomplished to date are unconvincing
regarding the noninferiority of carperitide compared with
standard therapy. Replication of the ASCEND-HF trial
using ANP rather than BNP could demonstrate the
benefit-risk ratio of carperitide but would be very costly.
No active carperitide trials are currently registered at Clinicaltrials.gov (accessed February 22, 2013), because the US
company affiliated with the Japanese manufacturer terminated their license agreement in January 2007, ending carperitide development in the US.64 The manufacturer of
carperitide (Daiichi Sankyo) did not communicate regarding any current or upcoming clinical trials in other
countries.
Urodilatin. Ularitide, the product of differential processing of the pro-ANP precursor in the kidney, acts on
NPR-A in the collecting duct, thereby increasing excretion
of water and sodium.13 Intravenous urodilatin, its synthetic
form, increased diuresis and natriuresis in compensated patients with HF to an extent similar to that of ANP, but
caused a greater and more sustained increase in cGMP.65
Compared with placebo, it decreased PCWP, decreased
MAP, and increased CI,66,67 while down-regulating the
RAAS and improving renal sodium excretion in healthy
volunteers.13 The most common adverse effect is dosedependent hypotension.67,68
The second Safety and Efficacy of an Intravenous Placebo-Controlled Randomized Infusion of Ularitide in a Prospective Double-blind Study in Patients with Symptomatic,
Decompensated Chronic Heart Failure (SIRIUS II), a double-blinded RCT of patients hospitalized with ADHF, compared urodilatin at various doses with placebo, evaluating
the coprimary end points of change in PCWP and selfassessed dyspnea at 6 hours.68 PCWP was significantly
decreased in the 15 ng kg1 min1 and 30 ng kg1
min1 intravenous urodilatin groups compared with
placebo (P ! .001 for both comparisons), and patientassessed dyspnea was significantly decreased in all 3 urodilatin groups compared with placebo (P ! .01 for all).
Efficacy and Safety of Ularitide for the Treatment
of Acute Decompensated Heart Failure (TRUE-AHF) is
an active trial of urodilatin registered at Clinicaltrials.gov
that will compare the effects of ularitide and placebo in
Carlson and Eckman
487
ADHF.69 The primary end point is moderate or marked
improvement in global assessment at 6, 24, and 48 hours.
The manufacturer of ularitide (Cardiorentis) did not communicate regarding any additional current or upcoming
clinical trials.
CD-NP. CD-NP (or ‘‘cenderitide’’) is a chimeric NP
synthesized from C-type natriuretic peptide (CNP) and Dendroaspis natriuretic peptide (DNP).56 CNP originates from
endothelial cells and activates NPR-B, resulting predominately in venodilation, and DNP was isolated from the green
mamba snake and activates NPR-A, with effects similar to
those of ANP and BNP. By fusing the DNP tail to CNP,
an NP is created that acts as a partial agonist of NPR-A
and an agonist of NPR-B.70 CD-NP decreases PCWP and
causes natriuresis and diuresis without a significant decrease
in MAP in animal models,71 and in healthy humans it increases urine output and urine sodium excretion and decreases serum aldosterone.72 It significantly decreases Cr
compared with furosemide in patients with stable HF.73
CD-NP is still in the early stages of investigation but has
been demonstrated to cause a dose-dependent decrease in
SBP (with some symptomatic hypotension) without evidence of worsening renal function compared with placebo
in patients with ADHF and renal dysfunction.74
The safety and pharmacokinetics of CD-NP are currently
being evaluated in patients with chronic HF.75e77 It may
prove to be beneficial for long-term therapy of HF, given
its antifibrotic and antihypertrophic effects.56 There are no
active trials of CD-NP in ADHF registered at Clinicaltrials.
gov (accessed February 25, 2013), nor did the manufacturer
of cenderitide (Nile Therapeutics) communicate regarding
any additional current or upcoming clinical trials.
Soluble Guanylyl Cyclase Agents
Cinaciguat. Cinaciguat (or BAY 58-2667) is an NOindependent sGC activator that is effective even in oxidative
conditions, unlike NTG and SNP (Fig. 2).13,16 The oxidative stress of many disease states, including hypertension,
coronary artery disease, and HF, renders sGC unresponsive
to NO, decreasing the efficacy of NTG and SNP. In comparison, cinaciguat activates sGC bound to oxidized Fe3þ or
without a bound heme moiety, thereby targeting diseased
vessels for vasodilatation.78 In healthy humans, cinaciguat
decreases diastolic blood pressure compared with placebo
without significantly decreasing SBP,79 and in patients
with ADHF it decreases PCWP and MAP and increases
CO without significantly changing Cr.79 Dose-dependent
hypotension is the most common adverse effect.80e82
Erdmann et al performed a double-blinded RCT examining the safety and efficacy of cinaciguat versus placebo in
139 patients hospitalized with ADHF.81 The primary end
point, PWCP at 8 hours, was significantly decreased in
the treatment group compared with placebo (7.7 mm
Hg vs 3.7 mm Hg; P ! .0001). Other significant hemodynamic effects at 8 hours included increased CI and
decreased MAP. There were no significant differences
488 Journal of Cardiac Failure Vol. 19 No. 7 July 2013
in dyspnea, renal function, or 30-day all-cause mortality between the 2 groups, but a significant increase in hypotension occurred in patients treated with cinaciguat (73% vs
26% with placebo), particularly at doses $200 mg/h, necessitating early termination of the trial.
The COMPOSE (A Placebo Controlled, Randomized,
Double-blind, Fixed-dose, Multicenter, Phase IIb Study to
Investigate the Efficacy and Tolerability of Cinaciguat
Given Intravenously to Subjects with ADHF) program, a series of randomized, double-blinded, placebo-controlled trials, evaluated the safety and efficacy of varying doses of
cinaciguat in patients with ADHF.82 COMPOSE 1 examined the hemodynamic effects of higher doses of cinaciguat
in patients with pulmonary artery catheterization (PAC),
and COMPOSE EARLY examined the effect on dyspnea
of the same doses of cinaciguat in patients without PAC.
Both trials were terminated early owing to higher rates of
hypotension in the treatment groups. COMPOSE 2, which
evaluated low-dose cinaciguat in patients with PAC, was
terminated owing to concerns that the study could not be
completed in a reasonable period. Statistical analysis was
not performed, but descriptive analysis of COMPOSE 1
showed a decrease in PCWP and RAP with cinaciguat,
and COMPOSE EARLY did not demonstrate any difference in dyspnea between the treatment arms. There was
difficulty recruiting patients who required PAC for hemodynamic monitoring, perhaps owing to the results of the Evaluation Study of Congestive Heart Failure and Pulmonary
Artery Catheterization Effectiveness (ESCAPE) trial.83 It
was also problematic to use dyspnea as a primary end point,
because it is often improved with initial therapy for ADHF
before randomization to a treatment arm.82
Cinaciguat may be of value in long-term therapy of
chronic HF,81 but there are no active trials registered at
Clinicaltrials.gov (accessed February 25, 2013). The manufacturer of cinaciguat (Bayer Healthcare) did not communicate regarding any current or upcoming clinical trials.
RAAS-Modifying Agents
Enalaprilat. Enalaprilat, the intravenous form of enalapril, is an angiotensin-converting enzyme inhibitor (ACEI) that decreases circulating angiotensin II and increases
bradykinin, which acts as a vasodilator.84 In observational
studies of patients with acute LV failure after MI, intravenous ACE-Is decreased PCWP, MAP, and SVR.85,86
Adverse effects include hypotension, renal dysfunction,
and angioedema.87
In a small double-blinded RCT of patients hospitalized
with acute cardiogenic pulmonary edema and stabilized
with furosemide, ISDN, and dobutamine, a small dose of
enalaprilat significantly decreased PCWP, MAP, and mean
pulmonary artery pressure (MPAP) at 8 hours and increased
renal blood flow at 4 hours compared with placebo (P !
.05 for all comparisons).88 No significant effect on CI
was apparent, and no adverse effects, including hypotension, occurred.
A similar nonblinded RCT in patients with refractory
ADHF not currently on an ACE-I evaluated the hemodynamic effects of enalaprilat bolus versus infusion and found
that the 2 treatments caused a similar decrease in PCWP,
MAP, and MPAP, although these effects were achieved
more rapidly and were more transient with the bolus
dose.89 Both groups met the primary hemodynamic end
point of a 20% decrease in PCWP by 30 minutes. Asymptomatic hypotension occurred, and change in Cr and potassium were not reported.
There are no current trials of enalaprilat in ADHF registered at Clinicaltrials.gov (accessed February 25, 2013), nor
was the manufacturer of enalaprilat (Vasotec IV; Valeant
Pharmaceuticals Internationa) aware of any current or upcoming clinical trials (personal communication, March
12, 2013). In general, enalaprilat is not indicated for early
management of ADHF, given its high risk for hypotension,87 though it can be considered in ACS with acute LV
dysfunction.90
Aliskiren. Aliskiren is an oral direct renin inhibitor
that blocks formation of angiotensin I and II without affecting kinin metabolism.16 Hemodynamically, it has been
shown to decrease SVR and PCWP in patients with decompensated HF,91 and its neurohormonal effects include decreased N-terminal prohormone of BNP (NT-proBNP),
plasma renin activity, and urinary aldosterone.92 Hyperkalemia, hypotension, and decreased renal function have been
reported as adverse effects.93
Results from Six Months Efficacy and Safety of
Aliskiren Therapy on Top of Standard Therapy, on Morbidity and Mortality in Patients With Acute Decompensated Heart Failure (ASTRONAUT), a multicenter
double-blinded RCT comparing aliskiren with placebo in
addition to standard therapy (including ACE-I or angiotensin receptor blocker) in patients hospitalized for
ADHF were recently reported.94 Therapy began during
hospitalization once the patient was stabilized and continued for 12 months after discharge.93 There was no significant difference between the 2 groups in the primary end
point of time to CV death or HF rehospitalization within
6 months. Post hoc subgroup analysis showed that patients
with diabetes tended to be less likely to benefit from aliskiren than those without diabetes (P 5 .08 for interaction),
consistent with the results of the Aliskiren Trial in Type 2
Diabetes Using Cardio-Renal Endpoints (ALTITUDE)
trial.95 It might be reasonable to consider a second ASTRONAUT trial that excludes patients with diabetes.
There are no other active trials of aliskiren in ADHF registered at Clinicaltrials.gov (accessed February 26, 2013),
and the manufacturer of aliskiren (Novartis) did not communicate regarding any current or upcoming clinical trials.
Other Vasodilators
Tezosentan. Tezosentan is an intravenous dual endothelin A- and B-receptor antagonist that preferentially
antagonizes the endothelin A-receptor, resulting in
Vasodilators in ADHF
vasodilation.87 Its development was prompted by the discovery that elevated plasma levels of endothelin-1 in patients with HF correlated with ventricular arrhythmias and
mortality.96 Early hemodynamic studies demonstrated
a dose-dependent increase in CI and decrease in
PCWP.96e98 Adverse effects include hypotension, worsening renal function, and headache.99e103
The Randomized Intravenous Tezosentan (RITZ) trials
compared the effect of relatively high-dose tezosentan
and placebo on various hemodynamic and clinical outcomes in patients with ADHF, including ADHF associated
with MI. RITZ-2 demonstrated a significant increase in CI
with tezosentan compared with placebo,99 but there was no
significant difference between the two arms in clinical end
points evaluated by the other RITZ trials.100e102
The Value of Endothelin Receptor Inhibition With Tezosentan in Acute Heart Failure Studies (VERITAS) compared the effect of a lower dose of tezosentan with
placebo on change in dyspnea, all-cause mortality, and
worsening HF in patients with ADHF, but they showed
no clinical benefit and were discontinued early for futility.103 No further trials of tezosentan in ADHF are registered at Clinicaltrials.gov (accessed February 26, 2013),
and the manufacturer of tezosentan (Actelion) is not aware
of any current or upcoming trials of the agent (personal
communication, February 19, 2013).
Relaxin. Relaxin, the hormone responsible for many
of the maternal hemodynamic changes in pregnancy, acts
as a systemic, renal, and coronary vasodilator in animal
models, thereby decreasing afterload, increasing CO, and
decreasing the risk of infarction during periods of myocardial ischemia.16,104 In humans with HF, relaxin levels were
increased and correlated with disease severity,105 and in patients with compensated HF it increased CI and decreased
PCWP, NT-proBNP, and Cr.106 No adverse effects have
been reported.106,107
Relaxin for the Treatment of Patients With Acute Heart
Failure (Pre-RELAX-AHF), an exploratory dose-finding
study, examined various clinical outcomes in patients with
acute HF and renal dysfunction treated with intravenous relaxin or placebo.107 Dyspnea at 6, 12, and 24 hours was moderately or markedly better in 40% of patients treated with
30 mg kg1 d1 relaxin compared with 23% treated with placebo (P 5 .044). This dose of relaxin was thought to be sufficiently effective and safe to warrant further study in ADHF.
Relaxin appeared to be less effective at higher doses, perhaps
owing to down-regulation of relaxin receptors at higher
plasma concentrations or other counterregulary effects.
RELAX-AHF-1 is a multicenter randomized doubleblinded placebo-controlled trial assessing symptom relief
and clinical outcomes in patients with acute HF and renal
dysfunction treated with relaxin or placebo for 48 hours.108
Coprimary end points are moderately or markedly improved dyspnea at 6, 12, and 24 hours and change in dyspnea through day 5. Safety end points include days alive and
out of hospital at day 60 and CV death or rehospitalization
for HF or renal failure through day 60 (the trial is powered
Carlson and Eckman
489
only to detect moderately large effects on long-term outcomes). RELAX-AHF-1 has been completed, but results
have not yet been published.109 There are no other active
trials of relaxin in ADHF registered at Clinicaltrials.gov
(accessed February 26, 2013), and the manufacturer of
the agent (Novartis) did not communicate regarding any
current or upcoming clinical trials.
Hydralazine. Hydralazine is a direct vasodilator with
an unknown mechanism of action that decreases afterload
and improves stroke volume, increases renal blood flow,
and has a moderate direct inotropic effect.29 Adverse
effects include hypotension, nausea, headache, and tachycardia.20 It is used in combination with long-term nitrate
therapy to prevent nitrate tolerance.110 In ADHF, it is
most often used as an oral vasodilator agent in combination
with nitrates during down-titration of SNP or inotropes.111
Given its hemodynamic effects, it may be efficacious as
an initial agent in ADHF, particularly in those with renal
dysfunction. The Goal-Directed Afterload Reduction in
Acute Congestive Cardiac Decompensation (GALACTIC)
trial will evaluate early goal-directed preload and afterload
reduction in patients hospitalized with acute HF and is currently recruiting participants.112 The open-label protocol involves initial therapy with sublingual and transdermal NTG
and oral hydralazine followed by titration of ACE-Is or
angiotensin receptor blockers to an SBP target of 90e110
mm Hg. The primary outcome is HF death or rehospitalization, and all-cause mortality or rehospitalization will
be evaluated as a secondary outcome. No other trial involving hydralazine in ADHF is currently registered at
Clinicaltrials.gov (accessed February 28, 2013).
Discussion
Therapy of ADHF continues to focus on symptom management. Along with diuretics and oxygen therapy, vasodilators are first-line agents for patients who are persistently
hypertensive, severely volume overloaded, or in acute pulmonary edema (see Fig. 5 for treatment algorithm).10,11,15
Vasodilators should also be used in those who do not respond adequately to intravenous diuretic therapy, whereas
inotropes are reserved for those with an inadequate response to diuretics and symptomatic hypotension. Those
who do not respond to vasodilator therapy may benefit
from an inotrope.
Of those vasodilators currently approved for use in
ADHF in the US, NTG may decrease intubation rates, occurrence of MI, and all-cause mortality in hypertensive
hypoxic patients.23,25 SNP did not improve all-cause mortality when originally studied in patients with LV dysfunction after MI33 but was associated with improved survival
in a more recent retrospective study of patients with
ADHF not due to MI, including normotensive patients.34
Nesiritide, despite initially promising data and inclusion
in earlier guidelines,10,15 was not superior to placebo in
the ASCEND-HF trial,53 so it is not included in the treatment algorithm in Figure 5. Minimal clinical data exist to
490 Journal of Cardiac Failure Vol. 19 No. 7 July 2013
support the use of carperitide, and it is not available for use
in the US.64 Among older agents not specifically approved
for use in ADHF, enalaprilat, though a potent vasodilator, is
not indicated in most patients owing to the high risk for hypotension,87 and hydralazine is generally used for transitioning to oral vasodilators rather than in the acute phase.111
Of the newer investigational agents, tezosentan and cinaciguat are no longer being investigated in ADHF owing to
hypotension and a lack of efficacy, respectively.82,103 CDNP is not registered for any further clinical trials in patients
with ADHF but is being investigated in chronic HF.73e75
The oral agent aliskiren has not been shown to be effective,
although there is some suggestion that it may benefit patients without diabetes.93 The oral agent hydralazine and
the IV agents relaxin and urodilatin are currently undergoing large multicenter double-blinded placebo-controlled
randomized trials examining clinical end points in patients
with ADHF.69,109,112 RELAX-AHF-1 (relaxin) has already
been completed, so data from this trial may be available
soon.109
In conclusion, of all the new vasodilatory agents developed
in the past decade, none have been shown to be as effective as
SNP or NTG. In VMAC, the only head-to-head trial of old and
new vasodilators, nesiritide was compared with less-thanoptimal doses of NTG and no significant difference in dyspnea
was found.39,41 Because NO donators are generally accepted
as the standard of care, it would be reasonable for new vasodilators to be tested against optimal doses of NTG and SNP. If
aliskiren, hydralazine, relaxin, or urodilatin is shown to be effective in clinical trials against placebo, a comparative effectiveness trial against SNP or NTG would be ideal, with
dyspnea, all-cause mortality, and HF readmission as coprimary end points and worsening HF and change in Cr as safety
end points. Until then, SNP and NTG continue to be first-line
vasodilators for use in ADHF.
Disclosures
None.
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